ABSTRACT Although the prevalence of smoking has declined over the past 50 years, large disparities in tobacco use remain across several subgroups, particularly disadvantaged and health compromised populations.1 Smokers living with HIV represent a major health disparity population in the United States (US) and the world more generally, and their unique healthcare needs are not being adequately addressed.2 For people living with HIV, smoking is related to poorer survival3,4 and among those who are adherent to their antiretroviral treatment regimens, smoking reduces life expectancy more than HIV.5?7 Major contributing factors to the maintenance and relapse of smoking among smokers living with HIV include increased exposure to multiple stressors associated with HIV, which often exacerbates anxiety/depression.8 The proposed intervention is informed, in part, by the success of our recently completed NIDA-funded R34 research project (1R34DA031038-01A1) in which we specified and tested in a small open trial, and then, a pilot randomized controlled trial (RCT) the feasibility, acceptability and initial efficacy of a 9-session, cognitive- behavioral-based intervention (named QUIT) to address smoking cessation by reducing anxiety and depression via specific emotional vulnerabilities (anxiety sensitivity, distress tolerance, and anhedonia). This intervention was specifically adapted and designed for smokers living with HIV. The results from this study revealed that, when compared to a brief enhanced treatment as usual control intervention (ETAU), patients assigned to QUIT achieved higher short-term (end of treatment [EOT]: QUIT: 59% vs. ETAU: 9%) and long- term (6-month follow-up: QUIT: 46% vs. ETAU: 5%) abstinence rates.9 We now propose to conduct a fully powered, 3-arm efficacy/effectiveness trial. We propose to enroll 180 smokers living with HIV across three implementation sites [(1) Infectious Disease Clinic, Massachusetts General Hospital (MGH), Boston, (2) Fenway Community Health, Boston, and (3) Thomas Street Health Center, Houston]. We seek to test the efficacy/effectiveness of the QUIT intervention at increasing point prevalence abstinence (primary outcome), by reducing anxiety and depression (secondary outcomes), and to determine if it outperforms an active, credible time-matched control, and a standard-of-care (SOC) control. The integration of resource utilization and cost-effectiveness analyses and the third SOC control arm support estimation of cost and effectiveness. If successful, the intervention would be ready for translation studies to examine implementation and dissemination into ?real-world? health, mental health, and social service settings.